Abstract A05: Developing patient derived xenograft (PDX) models for metastatic castration resistant prostate cancer (CRPC) during CYP17 inhibitor therapy

Abstract

Abstract Castration resistant prostate cancer (CRPC) is a deadly disease with a poor prognosis. Treatment options for CRPC patients involve taxanes or newly developed drugs targeting the androgen pathway or androgen synthesis, including CYP17 inhibitors. However, response to therapy varies dramatically among patients, which might be due, in part, to tumor heterogeneity. Therefore, understanding of the genomic landscape of CRPC would be important to help achieve better outcomes by developing personalized therapies. One challenge contributing to our lack of therapies for CRPC is a paucity of clinically relevant animal models predictive of response to therapy in human patients. The Prostate Cancer Medically Optimized Genome Enhanced Therapy (PROMOTE) study is a Mayo Clinic prospective trial designed for patients with metastatic CRPC who are treated with abiraterone acetate, a CYP17 inhibitor, over a 12 week period. Fresh tissue from metastatic lesions, primarily bone metastases, was obtained by needle core biopsy before and 12 weeks after initiating abiraterone acetate treatment. The samples were submitted for DNA and RNA sequencing and were also used to generate patient-derived xenograft (PDX) models. PDX models were developed by injecting biopsy samples subcutaneously or under the renal capsule in male non-obese diabetic (NOD)/severe combined immunodeficient (SCID) or NOD/SCID/IL-2γ-receptor null (NSG) mice implanted with 25mg testosterone pellets at the time of tissue implantation and 2 months later. Baseline samples from 103 unique patients as well as second samples from 61 patients post abiraterone acetate treatment were injected into approximately 600 mice. Of the samples for which pathology is currently available, 31% of the biopsies injected into mice were confirmed to include tumor tissue, which may be compared with a figure of 37.5% of samples sent for sequencing. Thus far, we have established 8 PDX models, four from baseline and four from post treatment samples. Seven models were derived from metastatic bone lesions, and one model from a liver metastasis. The tumor tissue in each model was expanded into a second of generation of mice and harvested when the tumors grew. No tumor was expanded more than four times. Genomic and transcriptomic analysis of xenograft tissue from different “generations” of xenograft expansion is ongoing and will be compared with similar data for the original biopsy. The evaluation of treatment response after exposure of these PDX models to different therapies including CYP19 inhibitors, AR blockers and taxanes is ongoing. These PDX models provide a tool for future drug testing and for studying mechanisms of resistance to therapy in CRPC. Citation Format: Fang Xie, Manish Kohli, Yin Ping, Rafael E. Jimenez, Richard M. Weinshilboum, Liewei Wang. Developing patient derived xenograft (PDX) models for metastatic castration resistant prostate cancer (CRPC) during CYP17 inhibitor therapy. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A05.